IE831610L

IE831610L - Pyridylpyrazoles

Info

Publication number: IE831610L
Application number: IE831610A
Authority: IE
Original assignee: Nativelle Sa Ets
Priority date: 1982-07-12
Filing date: 1983-07-11
Publication date: 1984-01-12
Also published as: ATE20063T1; IE56147B1; EP0099815B1; DE3363740D1; US4526895A; EP0099815A1; FR2529891B1; FR2529891A1

Abstract

The invention relates to new 3-pyridyl-5-alkoxy-pyrazole derivatives of the following formula: wherein R1 represents a 4-pyridyl, 3-pyridyl or 2-pyridyl group which is unsubstituted or which may be substituted with one or two lower alkyl groups; R2 represents a hydrogen atom or a lower alkyl group; and R3 represents a lower alkyl group, a phenyl group or an aralkyl group; and the acid addition salts thereof. The derivatives may be prepared by alkylation of a 3-pyridyl-5-pyrazolone. The derivatives are medicinally useful, particularly for the treatment of cardiac deficiency.

Description

fiht-S V The present invention relates to new pyrazole derivatives, and in particular to new 3-pyrldyl~5-alkoxy (or -phenoxy or benzyloxyj-pyrazole derivatives, a process for their preparation, and their raediclnal use.

In the field of medical compounds, various derivatives of pyrldinone 5 or pyridazlnone substituted with a pyrldyl group are known, for example, 5-pyr1dyl-2-pyrid1nones as 1n French Patents itos. 2,327,779,, 2,470,124 and 2,477,148, or 6-(pyr1dyl-4')-(2H)-3-pyridazinones as In French Patent No. 2,481,284. These compounds have the property of Increasing cardiac contractility and may be used as cardiotonic medications. On the other 10 hand, no con^arable pyrazole derivatives with such properties are known.

In addition, French Patent Mo. 2,167„997 describes l-amino-5-pyrazolone and l-anlno-5-methoxy pyrazole derivatives having a depressant activity on the central nervous system.

The work undertaken by applicants has shown that certain 15 5-alkoxy-pyrazole derivatives, substituted at the 3-pos1t1on with a pyrldyl group, possess interesting Inotropic properties enabling their medicinal use as cardiotonic medications.

Accordingly, one object of the present Invention is to provide new 3-pyr1dyl=5-alitoxy (or phanoxy or benzyloxy)=pyrazo1e derivatives, as 20 well as a process for the preparation of these compounds. til 2.

A further object of the present invention is to provide pharmaceutical compositions containing, as active constituents, 3-pyr1dyl-5-alkoxy (or -phenoxy or benzylQJty)-pyrazole derivatives, such compositions being particularly useful as cardiotonic agents.

These objects are achieved 1n the present Invention by a new 3-pyridyl~5-alkoxy (or -phenony or benzyloxyj-pyrazole derivative represented by the following general formula (I): (I) wherein Rj represents a 4=pyridyls 3~pyr1dyl or 2-pyrldyl group which Is 10 unsubstltuted or which may bs substituted with one or two lower alkyl groups with 1 to 4 carbon atoms, Rg represents a hydrogen atom or a lower alkyl group with 1 to 4 carbon atoms or a benzyl group and; R3 represents a lower alkyl group with 1 to 4 carbon atoms, a phenyl 15 group or a benzyl group; and the acid addition salts thereof. 3.

The expression "lower alkyl group" means a linear or branched alkyl group containing 1 to 4 carbon atoms, such as a methyl, ethyl, n-propyl, isopropyl group, etc.

When substituted with a lower alkyl group, the pyridyl 10 group can be, for example, a 2-methyl-4-pyridyl, 4-methyl~2~ pyridyl, 2,6-dimethyl-4-pyridyl, 2-ethyl-4-pyridyl, 2-iso-propyl-4-pyridyl, 2,6-dimethyl-3~pyridyl group, etc.

The invention preferably relates to the 3-pyridyl=5-alkoxy (or -pherioxy or benzyloxy) pyrazoles of the general formula (I) above wherein R-j is a 4-pyridyl, 3-pyridyl or 2-pyridyl group, R2 is a hydrogen atom or a methyl group, and R3 is a methyl, ethyl, isopropyl, phenyl or benzyl group.

The compounds of general formula (I) may exist under several equilibrium forms shown below: The invention also relates to the various equilibrium forms of said compounds. 4 The invention also extends to the 3-pyridyl-5-alkoxy (or -phenoxy or benzyloxy)-pyrazole salts of general formula (I) and in particular to the pharmaceutically acceptable salts obtained by action of a mineral or organic acid in accordance with the conventional methods of the art. The acid used may be selected from among hydrochloric acid, sulfuric acid, oxalic acid, tartaric acid, fumaric acid, lactic add, citric dcid0 phosphoric acid, p-tolueas sulfonic acid, fomie acid, hydrobromic acid, maleic acid, sulfamic acid, etc.

The 3-pyridyl-5-alf(oxy(or -phenoxy or benzylo*y)-pyrazoles of general formula (I) can be prepared in accordance with the invention by reacting, in a suitable organic solvent, an alkylation agent with S-pyridyl-S-pyraaolone of th® general formula (II): ;whareisi and have the same meaning es in fosmula (I). ;The alkylation la carried out ia solution, at ambient temperature, by meaas of as O-alkylatios ageat, for example diasomstliaae. ;Th® solvent ears, for exnnple, he beagg&e, tolueae, aa alcohol such as methanol, athanol or isopropaiiol, aa ether such as dimethyl ether, diethyl ether, dioxane, tetr&hfdro-furaa, etc., separately or in a mixture. ;It is preferable to carry out the alkylatiaa reaction of the 3-pyridyl-5-g»yrazo].one of formula (II) with an alcohol activated by means of triphaoylphosphine and ethyl azodiearbo&y! ate iss a neutral madium, by use of the method h ;of 0. Mitsunobu (Synthesis, (1981) page 1). This alkylation reaction is carried out by adding triphenylphosphine to a mixture of 3™pyridyl=5-pyrazolone of formula (II), alcohol and ethyl azodicarboxylate in an aprotic solvent such as tetrahydrofuran, dimethylforraamide or an aromatic hydrocarbon, at a temperature of between 0 and 20°C. The alkyla-tion reaction may also be carried out in converse by adding ethyl asodicarboxylate to a mixture of 3»pyridyl»5~pyraso-lone, alcohol and triphenylphosphine. In a third method of carrying out the alkylation reaction, 3-pyridyl-5-pyraaoione and alcohol may be added to a mixture of triphenylphosphine and ethyl azodicarboxylate previously cooled to a tempera" ture of between -20° and -10°C. ;The alcohol used for this reaction is selected in accordance with the substituent which it is desired to graft onto the oxygen atom of the pyrazolone nucleus, and can be represented by the formula R^-OE where is defined as above. For example, methanol, ethanol, isoaropasiol, stc„, may be used. ;Certain of the 3-pyridyl-5-pyra3oiones of general formula (II) are teown products, for ©sample 3~(«-pyridyl)-5-pyrasolone is described by H.L. Yale ete. si., JACS. 75, p. 1933 (1953). xn accordance with Yal© ex.. al., 3-($-pyridyl)-5-pyra»olosse can be prepared by reacting hydrasis® hydrate with ethyl isonicotinyl-aeetata in gv-propaaol. Similarly, the compounds of formula (II) can be prepared by reacting by a eycligation reaction in an acid mefiim, hydrazine hydrate with a ketoaster of general formula (XIX) ;Rj »C0-CHH2-COOC^Hg (III) ;where and Ej have the definitions given EshOTe. ;The following examples illustrate the invention without limiting the scope thereof. The structures of the derivatives have been confirmed by analysis and IR and WMR spectra. ;EXAMPLE 1 3=(4-pyridyl)-5~methoxy-pyrazole: ;300 ml of a solution of approximately 0.5N diazomethane in diethyl ether, freshly prepared, were gradually poured into a 1 liter flask containing 16.1 g of 3-(4-pyridyl)-5-pyrazolone in 150 ml of cold methanol under agitation. ;The reaction was allowed to take place for 24 hours at room temperature. The solvent was then evaporated until the contents were dry. The residue was dissolved in 50 ml of chloroform, and the solution was filtered to eliminate the remaining quantity of starting pyrazolone which was not reacted. The chloroform phase was then extracted with diluted sodium hydroxide. Diluted hydrochloric acid was added to the aqueous phase to bring the pH to 4, the solution was extracted with chloroform, and then crystallization was carried out in diisopropyl ether. ;In this manner, 9.1 g (yield 52%) of 3-(4—pyridyl)~5-methoxy pyrazole was obtained with the following characteristics : ;Melting point M.P. = 140°C ;IR spectrum (Mujol) v = 3500 to 2200, 1610, 1575, ;1550, 1520, 1400, 1040 cm"1 ;NMR spectrum ;6 = 3.9 (s,311) 6.4 (s, 1H) 7.7 (2H) 8.6 (2H) 12.7 (1H mobile) ppm (DMSOdg) ;The starting pyrazolone, recuperated by filtration of the chloroform solution, can be recycled to improve the yield. ;Hydrochloride: ;To a solution of 50 ml of isopropanol containing 5 g of 3-(4-pyridyl)~5-methoxy pyrazole, concentrated hydrochloric acid was added slowly until the pH was approximately 2 to 3. The hydrochloride crystals were precipitated and collected by filtration (yield 95%). ;Melting point M.P. = 205°C ;EXAMPLE 2 ;3-(4"pyridyl)-4-methyl-5-methoxy-pyrazole: ;1.5 mg of 3-(4-pyridyl)-4-methyl~5»pyrazolone, 2.3 g of triphenylphosphine and 0.27 g of methanol were placed in 30 ml of tetrahydrofuran. The mixture was cooled on an ice bath to 2°C and 1.6 g of ethyl azodicarboxylate dissolved in 9 ml of tetrahydrofuran was added dropwise. ;After the addition, the reaction medium was allowed to return to room temperature, then after 4 hours the insoluble material was filtered. Concentrated hydrochloric acid was added under agitation and the 3-(4-pyridyl)-4»methyl-5-methoxy pyrazole hydrochloride was filtered and purified by crystallization in methanol. ;8 ;Melting point M.P. = 263°C ;The base was extracted and obtained with a yield of 40% (0.65 g). ;Melting point M.P. = 140°C ;IR spectrum (Nujol) v = 3500 to 2500 (max. to 3300 and ;3150), 1615, 1590, 1550, 1515, 1410, 1170, 935, 830, 715 cm"1 ;EXAMPLE 3 ;3-(3-pyridyl)-4-methyl-5-methoxy-pyrazole: ;The process of Example 1 was repeated using 3-^pyridyl )-4~methyl-5~pyrazolone in order to obtain the desired product with a yield of 45%. ;Melting point M.P. = 134°c ;IR spectrum (Hujol) v = 3175, 1510, 1415, 1170, ;1020 cm"1 ;Hydrochloride: ;Melting point M.P. = 212-214°C ;EXAMPLE 4 ;3-(2-pyridyl)-4-methyl-5-methoxy-pyrazole: ;The process of Example 1 was repeated using 3-(2-pyri-dyl)-4-methyl-5-pyrazole in order to obtain the desired product with a yield of 40%. ;Hydrochloride: ;Melting point M.P. = 156-158°C ;EXAMPLE 5 ;3-(4-pyridyl)-4-benzyl-5-methoxy=pyrazole: ;0.8 g of diazomethane were reacted with 3.6 g of 3-(4-pyridyl)-4-benzyl=5-pyrazolone using the technique described in Example 1, in a mixture of tetrahydrofuran and methanol, for 24 hours. ;After evaporation of the solvent, extraction with methylene chloride, washing and trituration in diisopropyl ether, 2.2 g (yield 60%) of 3-(4-pyridyl)-4-benzyl~5-meth-oxy-pyrazole crystals were obtained which were purified by precipitation of the hydrochloride in isopropanol. ;IR spectrum (Wujol) v = 3380, 3160, 1635, 1605, 1580, ;1505, 1490 cm™1 ;Hydrochloride: ;Melting point M.P. = 186°C (dec.) ;EXAMPLE 6 ;3-(4-pyridyl)~4-methyl=5-ethoxy-pyrazole s ;5.3 g of 3-pyridy1-4-methy1-5-pyrazolone were placed under agitation in 120 ml of tetrahydrofuran, 8.6 g of tri-phenylphosphine and 1.8 ml of ethanol. The mixture was cooled on an ice bath to 2°C and 5.2 ml of ethyl azodicar-boxylate in solution in 20 ml of tetrahydrofuran was added ;10 ;dropwise. This mixture was allowed to react for 4 hours at room temperature. ;The pyrazolone precipitate which had not reacted was removed by filtration. The tetrahydrofuran was evaporated until the product was dry and the residue was dissolved with a solution of hydrochloric acid. After washing with methylene chloride, the 3-(4-pyridyl)-4-methyl-5-ethoxy pyrazole hydrochloride obtained was recrystallized in methanol, then transformed into the corresponding base. In this manner 3.4 g of product (yield 55%) was obtained. ;Melting point M.P. = 154-156°C ;IR spectrum (Mujol) v = 3000 to 3400, 1615, 1590, 1550, ;1510, 1355, 1170, 1040, 820, 715, 710 cm"1 ;The experiments carried out on the 3-pyridyl-5-alkoxy (or -phenoxy or benzyloxy) pyrazole type derivatives in accordance with the invantion have revealed interesting pharmacological properties8 in particular inotropic activity, suggesting their use in human and veterinary medicine as cardiotonic medications to be envisaged. ;The cardiac toxicity of the derivatives of general formula (I) is low, and it can for example be noted that in the test on the isolated guinea pig auricle, for a product dose of 3iao"^g/ml, no disorder in cardiac contraction was observed. ;Inotropic activity viae shown on the isolated guiasa pig auricle under the following experimental conditions: the survival liquid was composed of a carbogene tyrode solution (95% Oy * 5% CO2) thennostated at 30°C, the initial tension 11 placed on the auricles was 0.5 g, the volume of substance to be tested added to the bath was 0.5 ml, and the volume of the organ bath was 40 ml; the stabilization time of the organ was 1 hour. The force and frequency of contraction 5 were continuously recorded.

By way of example the 3™(4-pyridyl)-4-methyl~5-methoxy pyrazole described in Example 2 provided an increase of 120% in the force of maximum contraction under the conditions detailed above. This maximum was reached in 3 minutes and 10 an increase of 25% in the force of contraction still subsisted after 60 minutes.

These results show that the derivatives in accordance with the invention of general formula (I) can be used in medicine, more particularly for the treatment of cardiac 15 deficiency.

The derivatives o£ general formula (I) and their phar-maceutically acceptable salts can be administered in conventional forms, the active constituent being diluted in an appropriately selected pharmaceutical^ acceptable carrier, 20 for example, in the form of tablets, capsules, lozenges, suppositories, injectable solutions or syrups.

By way of example, tablets can be prepared by mixing the derivative of general formula (X) or one of its salts, with one or several solid diluents, such as lactose, 25 mannitol, starch, polyvinylpyrrolidone, magnesium stearate, talc, etc., Where necessary, the tablets may comprise several layers superposed around a nucleus, in accordance with conventional techniques, in order to ensure progressive release or a delayed effect of the active ingredient. The 30 coating may, for example, be composed of on® or several 12 layers of polyvinyl acetate, carboxymethylcellulose or cellulose acetophthalate.

The derivative of the invention may also be administered in the form of a syrup or drinkable solution obtained 5 by dissolving the derivative of formula (I), as necessary in the form of a pharmaceutically acceptable salt, in water or glycerol, for example, and, as necessary, adding a conventional additive such as a sweetener and an antioxidant:.

Injectable solutions can be prepared using well-known 10 techniques and can be composed, for example, of a solution containing a derivative of formula (I) or one of its pharmaceutically acceptable salts, dissolved in bidistilled water, a hydroalcoholic solution, propylene glycol, etc., or a mixture of such solvents. Where necessary, an appropriate 15 additive such as a preservative may be added.

An effective dosage amount of active compound can easily be determined by a clinician upon consideration of all criteria such as the route of administration, the particular compound used, the condition of the patient, the 20 duration of the treatment and utilizing the best judgment of the clinician.

While the invention has been described in detail and with reference to specific embodiments thereof, it will be apparent to one skilled in the art that various changes and 25 modifications can be made therein without: departing from the spirit and scope thereof. 13

Claims

1. A 3-pyridyl-5-alkoxy (or -phenoxy or benzyloxyj-pyrazole derivative represented by the following formula (I): wherein represents a 4-pyridyl, 3-pyridyl or 2-pyridyl group which is unsubstituted or which may be substituted with one or two lower alkyl groups with 1 to 4 carbon atoms, Rg represents a hydrogen atom or a lower alkyl group with 1 to 4 carbon atoms or a benzyl group; and represents a lower alkyl group fith 1 to 4 carbon atoms, a phenyl groun or a benzyl group; and the acid addition salts thereof.

2. The derivative of claim 1, wherein R^ is a 4-pyridyl, 3-pyridyl or 2-pyridyl group.

3. The derivative of claim 1, wherein R2 is a hydrogen atom or a methyl group.

4. The derivative of claim 1, wherein R3 is a methyl group, an ethyl group, an isopropyl group, a phenyl group or a benzyl group.

5. The derivative of claim 1, wherein said derivative is 3-(4-pyridyl)-4-methyl=5-methoxy-pyrazole or the acid salts thereof. 14

6. A process for the preparation of the derivative of claim 1, wherein a 3-pyridyl-5-pyrazolone of the following formula (II) is reacted with an alkylation agent in an appropriate solvent.

7. The process of claim 6, wherein the alkylation agent is diazoraethane.

8. The process of claim 6, wherein the alkylation is carried out by an alcohol activated by means of triphenyl-phosphine and ethyl azodicarboxylate in a neutral medium.

9. A pharmaceutical composition comprising a 3-pyri-dyi-5-alkoxy-pyrazole derivative represented by the following formula (I): wherein R1 represents a 4-pyridyl, 3-pyridyl or 2-pyridyl group which is unsubstituted or which may be substituted with one or two alkyl groups; R2 represents a hydrogen atom or a C-j_4 alkyl group; and R3 represents a alkyl (II) (I) 15 group, a phenyl group or a benzyl group; or a pharmaceutical^ acceptable salt thereof as an active ingredient, and a pharmaceutical^ acceptable excipient.

10. A pharmaceutical composition comprising a 3-pyridyl-5-alkoxy-pyrazole derivative represented by the following formula (I): wherein R-^ represents a 4-pyridyl, 3-pyridyl or 2-pyridyl group; R2 represents a hydrogen atom or a alkyl group; and R3 represents a alkyl group, a phenyl group or a benzyl group; or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient.

11. A pharmaceutical composition comprising a 3-pyridyl~5-alkoxy-pyrazole derivative represented by the following formula (I): wherein R^ represents a 4-pyridyl, 3-pyridyl or 2-pyridyl group which is unsubstituted or which may be substituted with one or two C14 alkyl groups; R2 represents a hydrogen (I) R. (I) 16 atom or a methyl group; and R3 represents a C14 alkyl group, a phenyl group or a benzyl group; or a pharmaceutical^ acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient.

12. A pharmaceutical composition comprising a 3-pyridyl~5-alkoxy*-pyrazole derivative represented by the following formula (I): wherein R^ represents a 4-pyridyl, 3-pyridyl or 2-pyridyl group which is unsubstituted or which may be substituted with one or two C-j.^ alkyl groups; R^ represents a hydrogen group, an ethyl group, an isopropyl group, a phenyl group or a benzyl group; or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient.

13. A pharmaceutical composition comprising 3-(4-pyri-dyl)-4-methyl-5-methoxy-pyrazole or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable excipient. (I) atom or a group; and R^ represents a methyl 17

14. A process for the preparation of compounds of formula (I) as defined in claim 1, substantially as hereinbefore described by way of Example.

15. Compounds of the formula (I) as defined in claim 1, whenever prepared by a process as claimed in any of claims 6 to 8 or 14. Dated this the 11th day of July, 1983. TOXINS & CO., Applicant's Agents, (Signed) ^ 5, Dav^mouth Koad, DUBLIN 6. 18